Immune dysregulation due to bi-allelic mutation of the actin remodeling protein DIAPH1.

Children with severe inflammatory diseases are challenging to diagnose and treat, and the etiology of disease often remains unexplained. Here we present DIAPH1 deficiency as an unexpected genetic finding in a child with fatal inflammatory bowel disease who also displayed complex neurological and developmental phenotypes. Bi-allelic mutations of DIAPH1 were first described in patients with a severe neurological phenotype including microcephaly, intellectual disability, seizures, and blindness. Recent findings have expanded the clinical phenotype of DIAPH1 deficiency to include severe susceptibility to infections, placing this monogenic disease amongst the etiologies of inborn errors of immunity. Immune phenotypes in DIAPH1 deficiency are largely driven aberrant lymphocyte activation, particularly the failure to form an effective immune synapse in T cells. We present the case of a child with a novel homozygous deletion in DIAPH1, leading to a premature truncation in the Lasso domain of the protein. Unlike other cases of DIAPH1 deficiency, this patient did not have seizures or lung infections. Her major immune-related clinical symptoms were inflammation and enteropathy, diarrhea and failure to thrive. This patient did not show T or B cell lymphopenia but did have dramatically reduced naïve CD4+ and CD8+ T cells, expanded CD4-CD8- T cells, and elevated IgE. Similar to other cases of DIAPH1 deficiency, this patient had non-hematological phenotypes including microcephaly, developmental delay, and impaired vision. This patient's symptSoms of immune dysregulation were not successfully controlled and were ultimately fatal. This case expands the clinical spectrum of DIAPH1 deficiency and reveals that autoimmune or inflammatory enteropathy may be the most prominent immunological manifestation of disease.

First Report of a Paediatric Collision Tumour in the Liver Recognised After Liver Transplantation: Blissful Ignorance Has Benefits!

Liver tumours are uncommon in the paediatric population, constituting 1-2 % of all paediatric tumours and 4% of all paediatric liver tumours. Hepatoblastoma followed by hepatocellular carcinoma is the most common tumours in this age group. Simultaneous development of two discrete liver tumours of distinct histologies (collision tumour) has been occasionally reported in adults but never in children. We hereby present the first reported case of hepatic collision tumours (hepatocellular carcinoma and cholangiocarcinoma) in the explant liver of a child who underwent living donor liver transplantation for end-stage liver disease and severe hepatopulmonary syndrome. The manuscript describes the clinical, radiological and histopathological findings of this case and also highlights the dilemma associated with management of this case had the diagnosis been made in the preoperative setting and also about the proposed management plan for this case in the postoperative period.

Living-Donor Liver Transplantation for Late-Onset Lysosomal Acid Lipase Deficiency.

Late-onset liposomal acid lipase deficiency (LAL deficiency), previously known as Cholesteryl ester storage disease (CESD) is a rare genetic lysosomal storage disorder caused by deficiency of lysosomal acid lipase (LAL) due to mutations in the LIPA gene. LAL deficiency is a systemic disease that leads to the accumulation of fat and inflammation in the liver, premature atherosclerosis and gastrointestinal disease. Most of the patients require liver transplantation due to decompensated cirrhosis. Enzyme replacement therapy has been approved and is available in many countries. Here we describe a 16-year-old patient who was diagnosed to have late-onset LAL deficiency when he presented to us with ESLD. Subsequently, he underwent a living-donor liver transplant (LDLT) successfully. We discuss the ethical dilemmas in considering LDLT for LAL deficiency.